Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor cloned in 1990 as a receptor responsive to peroxisome proliferator, forms a heterodimer with other nuclear receptor, retinoid X receptor (RXR), and activates various target genes as a transcription factor. PPAR comprises three kinds of subtypes (PPARα, β(δ), γ), and it has been clarified that fibrate, which is a therapeutic drug for hyperlipidemia, acts as a ligand for PPARα, and a thiazolidine derivative, which is an insulin sensitizer, acts as a ligand for PPARγ.
Fibrate is a pharmaceutical agent widely used as a therapeutic drug for hyperlipidemia, and clofibrate, aluminum clofibrate, simfibrate, clinofibrate and the like have been heretofore used. At present, bezafibrate (Bezatol SR (registered trademark), Bezalip (registered trademark)) and fenofibrate (lipantil (registered trademark)), which are called the second generation, have been generally used.
Fibrate is known to regulate expression of genes (acyl CoA synthase, lipoprotein lipase, fatty acid transport protein and the like) relating to the metabolism of fatty acid and apolipoprotein (AI, AII, AV, CIII) genes involved in triglyceride (TG) and cholesterol metabolism, by activation of PPARα, decreases TG and LDL cholesterol and increases HDL cholesterol. Thus, fibrate is known to be highly effective as a therapeutic drug for hyperlipidemia.
However, since conventional fibrate shows a weak PPARα agonist activity (EC50) of a μmol/L order (not less than 30 μmol/L), the dose needs to be as high as 200-1500 mg/day. In addition, various side effects such as digestive symptoms such as gastric distress, feeling of sickness and the like, skin symptoms such as anthema and the like, liver dysfunction and pancreatitis have been reported (foregoing from lipantil (registered trademark) package insert), and there is a room for further improvement as a pharmaceutical agent having a PPARα agonist action.
From the above, a pharmaceutical use as a compound superior in the pharmacological action based on PPARα activation (TG lowering action, LDL-C lowering action, HDL-C increasing action, anti-atherogenic action and the like) is expected by creating a compound capable of specifically activating PPARα than conventional fibrates.
Given such background, various carboxylic acid derivatives have been reported in recent years with regard to PPARα agonists. For example, patent reference 1, non-patent reference 1 and non-patent reference 2 have reported (phenylthio)acetic acid derivatives, patent reference 2 and non-patent reference 3 have reported 3-phenylpropionic acid derivatives, patent reference 3 and non-patent reference 4 have reported phenoxyacetic acid derivatives, patent reference 4 has reported phenoxyacetic acid derivatives, patent reference 5 and non-patent reference 5 have reported 2,2-dichloroalkane carboxylic acid derivatives, patent reference 6 has reported 1,3-dioxane-2-carboxylic acid derivatives, and patent reference 7 has reported phenoxyacetic acid derivatives, but no description of (1,3-thiazol-2-yl)thioacetic acid derivatives like the compound of the present invention is provided.    patent reference 1: WO00/23407    patent reference 2: WO00/75103    patent reference 3: WO02/38553    patent reference 4: WO02/28821    patent reference 5: WO96/15784    patent reference 6: WO01/90087    patent reference 7: WO02/096894    non-patent reference 1: J. Med. Chem., 42, 3785 (1999)    non-patent reference 2: Bioorg. Med. Chem. Lett., 11, 1225 (2001)    non-patent reference 3: Bioorg. Med. Chem. Lett., 12, 333 (2002)    non-patent reference 4: J. Med. Chem., 46, 5121 (2003)    non-patent reference 5: Am. J. Physiol., 283 (3, Pt. 2), H949 (2002)